The amino acid sequence of leuteinizing hormone releasing hormone (LH-RH) has been determined by Matsuo et al., B.B.R.C. 43(6) 1334(1971) and Burgus et al., Proc. Natl. Acad. Sci. 69 278(1972) to be p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2. Shortly after the elucidation of the amino acid sequence of LH-RH it was found that changes of the amino acid residue in 2-position (His) markedly altered the activity of the decapeptide by diminishing or eliminating agonist activity with enhanced LH-RH antagonism. Rees et al., J. Med. Chem. 17(9) 1016(1974) found that [D-Trp.sup.2 ]-LH-RH and [D-Phe.sup.2 ]-Lh-RH antagonized LH release induced by LH-RH in vitro at a ratio of 1000:1 and 200:1, respectively, of their agonist (releasing) activity. Substitution of either L- or D-aliphatic amino acids in 2-position failed to afford products with meaningful antagonist activity. Beattie et al., J. Med. Chem. 18(12)1247(1975) report ten analogs of LH-RH substituted in 2-position with D-Phe, D-p-F-Phe or D-p-Cl-Phe and at 6 -position with either a D-amino acid (D-Ala, D-Leu, D-Ser, D-Arg, D-(Ph)Gly, D-Lys) or 2-Me-Ala. The data demonstrated that no D-amino acid or non-asymmetric amino acid substitution in 6-position was more effective than D-Ala in potentiating antiovulatory activity. Rivier et al., Life Sciences 23 869(1978) report various polysubstituted LH-RH analogs such as [D-pGlu.sup.1, D-Phe.sup.2, D-Trp.sup.3,6 ]-LH-RH which afforded an IDR.sub.50 (inhibitory molar dose ratio-antagonist (LH-RH) of 3/1, in vitro. The effective dose for in vivo inhibition of ovulation was 20-25 mg when administered at noon of proestrus.
In studying LH-RH agonist analogues, Yabe et al. Chem. Pharm. Bull. 24(12) 3149(1976) noted that Nal(1).sup.3 -LH-RH had 187.1 percent the potency of LH-RH as a leuteinizing hormone (LH) releasing agent.